Das K C, Lewis-Molock Y, White C W
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206, USA.
Mol Cell Biochem. 1995 Jul 5;148(1):45-57. doi: 10.1007/BF00929502.
TNF alpha and IL-1 each can activate NF-kappa B and induce gene expression of manganese superoxide dismutase (MnSOD), a mitochondrial matrix enzyme which can provide critical protection against hyperoxic lung injury. The regulation of MnSOD gene expression is not well understood. Since redox status can modulate NF-kappa B and potential kappa B site(s) exist in the MnSOD promoter, the effect of thiols (including NAC, DTT and 2-ME) on TNF alpha and IL-1 induced activation of NF-kappa B and MnSOD gene expression was investigated. Activation of NF-kB and increased MnSOD expression were potentiated by thiol reducing agents. In contrast, thiol oxidizing or alkylating agents inhibited both NF-kappa B activation and elevated MnSOD expression in response to TNF alpha or IL-1. Since protease inhibitors TPCK and TLCK can inhibit NF-kappa activation, we also investigated the effect of these compounds on MnSOD expression and NF-kappa B activation. TPCK and TLCK each inhibited MnSOD gene expression and NF-kappa B activation. Since the MnSOD promoter also contains an AP-1 binding site, the effect of thiols and thiol modifying agents on AP-1 activation was investigated. Thiols had no consistent effect on AP-1 activation. Likewise, some of the thiol modifying compounds inhibited AP-1 activation by TNF alpha or IL-1, whereas others did not. Since diverse agents had similar effects on activation of NF-kappa B and MnSOD gene expression, we have demonstrated that activation of NF-kappa B and MnSOD gene expression are closely associated and that reduced sulfhydryl groups are required for cytokine mediation of both processes.
肿瘤坏死因子α（TNFα）和白细胞介素-1（IL-1）均可激活核因子κB（NF-κB）并诱导锰超氧化物歧化酶（MnSOD）的基因表达，MnSOD是一种线粒体基质酶，可对高氧肺损伤提供关键保护。MnSOD基因表达的调控机制尚不完全清楚。由于氧化还原状态可调节NF-κB，且MnSOD启动子中存在潜在的κB位点，因此研究了硫醇（包括N-乙酰半胱氨酸、二硫苏糖醇和2-巯基乙醇）对TNFα和IL-1诱导的NF-κB激活及MnSOD基因表达的影响。硫醇还原剂可增强NF-κB的激活及MnSOD表达的增加。相反，硫醇氧化剂或烷基化剂可抑制TNFα或IL-1诱导的NF-κB激活及MnSOD表达的升高。由于蛋白酶抑制剂对氯苯甲酰-L-苯丙氨酰氯甲酮（TPCK）和对甲苯磺酰-L-赖氨酸氯甲酮（TLCK）可抑制NF-κB的激活，我们还研究了这些化合物对MnSOD表达及NF-κB激活的影响。TPCK和TLCK均可抑制MnSOD基因表达及NF-κB激活。由于MnSOD启动子还包含一个激活蛋白-1（AP-1）结合位点，因此研究了硫醇及硫醇修饰剂对AP-1激活的影响。硫醇对AP-1激活无一致影响。同样，一些硫醇修饰化合物可抑制TNFα或IL-1诱导的AP-1激活，而另一些则无此作用。由于多种试剂对NF-κB激活及MnSOD基因表达有相似影响，我们证明NF-κB激活与MnSOD基因表达密切相关，且两个过程的细胞因子介导均需要还原型巯基基团。
